Method and apparatus for treatment of focal disease in hollow tubular organs and other tissue lumens

ABSTRACT

The present invention provides a technique for treating diseased portions of tissue lumens by the focal introduction of at least one therapeutic agent at the diseased region. A catheter is positioned in a lumen such that first and second expansile members surround the diseased portion of tissue. The expansile members are expanded to occlude the diseased region and a therapeutic agent is introduced to the occluded diseased region via the catheter. The catheter is allowed to remain in place for a therapeutically effective period of time to allow the therapeutic agent to contact the diseased portion for such a period of time. The catheter arrangement also can be used to occlude a diseased region, remove physiological fluid from the occluded region and subsequently to disrupt the diseased region and/or apply the therapeutic agent. The therapeutic agent can be selected to suppress cell proliferation in the diseased region, and the occluded region can be treated with a medicament to promote vessel healing. The occluded region also can be paved with polymeric material. Finally, the expansile members are contracted and the catheter is removed.

This application is a continuation of application Ser. No. 08/101,966(filed Aug. 4, 1993 and issued as U.S. Pat. No. 5,328,471), which is acontinuation of application Ser. No. 08/014,043 (Feb. 5, 1993,abandoned), which is a continuation of application Ser. No. 07/869,907(Apr. 15, 1992, abandoned), which is a continuation of application Ser.No. 07/759,048 (Sep. 5, 1991, abandoned), which is a continuation ofapplication Ser. No. 07/485,287 (Feb. 26, 1990, abandoned).

BACKGROUND OF THE INVENTION

This application relates to the localized treatment of disease in hollowtubular organs, such as blood vessels, and other tissue lumens. Thetreatment regime involves the introduction of a therapeutic agent into aregion of the tissue lumen defined by two expansile members. Inparticular, the application relates to the use of this technique toperform "bloodless angioplasty" in blood vessels having flowrestrictions due to atherosclerotic plaque.

Within the bodies of animals, including man, there exist those organs orstructures having hollow or tubular geometry, for example blood vesselssuch as arteries or veins, the gut and the bladder. In addition, thereexist many "solid" organs which possess true spaces such as cavities,cavernous sinuses, lumens etc. These "solid" organs include the heart,liver, kidney and pancreas. Finally disease processes (e.g., necrotictumors) and traumatic injury may create spaces within otherwise solidorgans.

The lumens afforded by these various types of spaces can be affected bya variety of disease processes. For example, the lumen may be occludedthus limiting or preventing flow through the lumen. Since the lumen ofmany hollow organs serves a vital function, e.g., the transit conduitfor blood, urine, bile or food, this restriction of flow through thelumen is detrimental. A particular example is the development and growthof an occluding atheroma (atherosclerotic plaque) in an artery, therebyreducing the blood flow through the artery.

In many cases, the wall of a tissue lumen has a significant barrierfunction as well as acting as a conduit for fluids. As an example, in ablood vessel, the "intima" or endothelial lining layer separatesoverflowing blood from the underlying middle or "media" portion of thevessel. Since the media is highly thrombogenic this separation isnecessary to avoid clotting of the blood in normal blood vessels.Further, the media, if exposed to overflowing blood as a result ofviolation of the intimal barrier may be stimulated by platelets andmacrophages in the blood, leading to smooth muscle cell proliferationand a regeneration of the stenosis. Disease conditions, such as advancedulcerated atherosclerotic lesions, and in some instances interventiontechniques, can disrupt this barrier layer leading to local bloodclotting, inflammation and diffusion of growth stimulating factors suchas platelet derived growth factor (PDGF), interleukin-1, andmacrophage-derived growth factor (MDGF) into the media with subsequentactivation, migration and proliferation of smooth muscle cells in theintima leading to a local buildup and regrowth of the stenosis.

Disease processes can also lead to the alteration of the structureand/or function or the tissue surrounding the lumen. For example, partof the tissue wall may be replaced by a cancerous/tumorous region or byan inflammatory zone. In advanced atherosclerosis, the vessel wall isreplaced with lipid and inflammatory cell infiltrates, newlyproliferated smooth muscle cells, fibrotic collagen and other connectivetissue and dense calcium deposits. This replacement dramatically altersvessel function preventing (1) vessel vasomotion, i.e., the abilitydilate or contract thereby altering blood flow based on organ metabolicdemands; (2) normal flux in cellular nutrients into and through thevessel, i.e., glucose and oxygen as well as outflow of metabolicbreakdown products/wastes; (3) normal release of downstream actingvasoreactive substances, i.e., endothelial derived relaxation factor(EDRF); and (4) normal metabolism of locally acting growth substancessuch as PDGF made by endothelial cells, thereby altering local vesselwall growth control and repair capabilities.

Further, even if there is not a change in the apparent makeup of thetissue surrounding the lumen, the metabolism of these cells may change.Thus, the production of required mediators such as growth factors andhormones may be disturbed. This also happens in atherosclerosis, wheretrans-vessel wall flow of nutrients, oxygen, lipid compounds, and growthfactors are typically altered.

Although the types of problems which can occur in hollow organs andtissue lumens are generally recognized, the treatment regimes availablegenerally attempt to treat the symptom rather than the underlying cause.This has a number of drawbacks, as can be illustrated usingatherosclerosis as an example.

In atherosclerosis, the overall problem is the progressive build-up ofan atheroma or atherosclerotic plaque at a focal location on an arterywall. The plaque is a complex of multi-component three dimensionalstructure composed of proliferating smooth muscle cells, stimulatedmacrophages and other inflammatory cells, chemically modified lipidcomponents, i.e., cholesterol, oleate:linoleate esters, stiff connectivetissue, i.e., collagen, and calcium. The distribution of plaque in thevessel wall is such that the bulk of the disease mass resides as anobstructing growth or "bulge" within the vessel lumen. This leads toreduced blood flow across the point of the plaque and subsequent reduceddownstream blood flow. If such a restriction of flow occurs in the vitalarterial beds, e.g., the coronary arteries in the heart or the carotidartery in the neck, the reduction of blood flow can lead to angina inthe heart or a transient ischemic attack (TIA) in the brain. Completeflow cut-off will lead to heart attack or stroke, respectively.

Treatment for atherosclerosis has progressed from coronary artery bypassgrafting (CABG) to catheter based techniques such as percutaneoustransluminal coronary angioplasty. (PTCA) Thus, the state of the art hasgone from merely by-passing the problem region to actually attempting torelieve the effects of the obstruction by direct attack and dilatationof the lesion. These attempts have led to the development of variouscatheter designs and treatment techniques. For example, U.S. Pat. No.4,636,195 to Wolinsky describes the use of a catheter with two occludingballoons and a conduit for supplying a solubilizing agent to dissolvethe plaque. A central balloon is included to force the solubilizingagent into the plaque. U.S. Pat. No. 4,610,662 of Weikl et al. describesa catheter which isolates the diseased region using a catheter havingtwo expandable balloons and then introduces a chemical, such asdigestive enzymes, for dissolving the plaque between the balloons. Asimilar approach to the treatment of gall stones is disclosed in U.S.Pat. No. 4,781,677 to Wilcox.

These approaches, however, like the basic technique of angioplastyitself, make no attempt to address the underlying pathophysiology thatis operant or to otherwise biomanipulate the lesion. Thus, there is noeffort to induce lesion regression or resorption or the fulldisappearance of the lesion with healing and replacement of the diseasedwall segment with a healthy wall segment with normal vessel componentsand function. The present invention fills this need, by providing forthe focal administration of therapeutic agents to a diseased region,either alone or in conjunction with a physical attack (such as PTCA) onthe diseased region.

SUMMARY OF THE INVENTION

In accordance with the claimed invention, diseased portions of tissuelumens can be advantageously treated by the focal introduction of atleast one therapeutic agent to the lumen at the diseased point. This canbe accomplished by

(a) introducing a catheter into the tissue lumen, said cathetercomprising first and second expansile members and means for supplyingtherapeutic agent into a space between said first and second expansilemembers, and said catheter being positioned such that said first andsecond expansile members are disposed on opposite sides of the diseasedregion;

(b) expanding the expansile members to occlude the diseased region ofthe tissue lumen;

(c) introducing therapeutic agent to the occluded diseased region viasaid means for supplying therapeutic agent;

(d) allowing the catheter to remain in place for a therapeuticallyeffective period of time;

(e) contracting the expansile members; and

(f) removing the catheter.

A particularly preferred application of the method of the invention is"bloodless angioplasty." In this application, the occluded diseasedregion is washed to remove blood prior to the introduction of thetherapeutic agent. Then, the diseased region is treated with atherapeutic agent to suppress cell proliferation in the diseased region.The plaque is then disrupted, for example by conventional balloonangioplasty, atherectomy, laser plaque removal or ablation. Finally, theoccluded region may be treated with a medicament to promote vesselhealing and sealed with a polymeric coating. Because blood does not comeinto contact with the media which may be exposed during the disruptionof the lesion, the risks of clotting in this technique are reduced.Further, the "wounded," stimulated and exposed media smooth muscle cellsare not exposed during the immediate post-dilatation time when they aremost sensitive to activation and stimulation by various factors found inthe blood, the predominant mechanism leading to restenosis and long termPTCA failure. Thus, the anti-proliferative therapy will further reducethe likelihood of long term restenosis, through inhibition of smoothmuscle cell proliferation which is maximum during the first 12 to 24hours following treatment.

The method of the invention is advantageously practiced using aspecially adapted catheter comprising at least two expansile members, areservoir containing the therapeutic agent and a least one conduit forsupplying therapeutic agent to the between the two expansile members.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows two views of a catheter device in accordance with theinvention;

FIG. 2 shows a catheter device in accordance with the invention;

FIG. 3 shows the steps for performing "bloodless angioplasty" inaccordance with the invention;

FIG. 4 shows a catheter device in accordance with the invention;

FIG. 5 shows two views of a catheter device in accordance with theinvention;

FIG. 6 shows two views of a catheter device in accordance with theinvention;

FIG. 7 shows a catheter device in accordance with the invention.

DETAILED DESCRIPTION OF THE INVENTION

As used in the specification and claims of this application, the term"therapeutic agent" refers to substances which alter the metabolism ofthe cells or reduce the tendency for thrombosis within the diseasedportions of the tissue. Examples for use in coronary artery applicationsare vasodilating agents i.e. nitrates and calcium channel blockingdrugs; anti-proliferative agents i.e. colchicine and alkylating agents;intercalating agents; growth modulating factors such as interleukins,transformation growth factor b, congeners of platelet derived growthfactor and monoclonal antibodies directed against growth factors;anti-thrombotic agents, e.g., anti-GIIb/3a, trigramin, prostacyclin andsalicylates; thrombolytic agents e.g. streptokinase, urokinase, tissueplasminogen activator (TPA) and anisoylated plasminogen-streptokinaseactivator complex (APSAC); anti-inflammatory agents, both steriodal andnon-steroidal and other agents which may modulate vessel tone, function,arteriosclerosis, and the healing response to vessel or organ injurypost intervention. Anti-proliferative drugs or high efficacyanti-inflammatory drugs are also useful for treatment of focalvasculitides or other inflammatory arteritidies, e.g., granulomatousarteritis, polyarteritis nodosa, temporal arteritis and Wegner'sgranulomatosis. Anti-inflammatory agents are also useful in connectionwith indications such as inflammatory bowel disease, Crohn's disease,ulcerative colitis and focal GI inflammatory diseases. In otherapplications, adhesives may be introduced in accordance with theinvention to help heal dissections, flaps and aneurysms. Exemplaryadhesives include cyanoacrylates, gelatin/resorcinal/formol, musseladhesive protein and autologous fibrinogen adhesive. The term"therapeutic agents" does not encompass solubilizing or dissolvingagents which disrupt the atherosclerotic plaque.

Catheter devices in accordance with the invention may include a varietyof variations and modifications as will be discussed in greater detailbelow. In general, however, the catheters bodies for use in thisinvention can be made of any known material, including metals, e.g.steel, and thermoplastic polymers, and may be continuous tubes or woven,spring-like structures. The expansile members balloons may be made fromcompliant materials such as latex or silicone, or non-compliantmaterials such as polyethyleneterephthalate (PET), polyvinylchloride(PVC), polyethylene or nylon. The catheter may also include markers inone or more locations to aid in locating the catheter. These markers canbe, for example, fluoroscopic radio-opaque bands affixed to the tubularbody by heat sealing.

As used in the specification and claims of this application, the term"paving" refers to the application of a conforming polymeric coating tothe surface of the tissue lumen. Thus, in "paving," a polymericmaterial, either in the form of a monomer or prepolymer solution or asan at least partially pre-formed polymeric product, is introduced intothe lumen of the blood vessel and positioned at the point of theoriginal stenosis. The polymeric product is then reconfigured to conformto and maintain intimate contact with the interior surface of the bloodvessel such that a paving and sealing coating is achieved. The polymericpaving and sealing material may incorporate therapeutic agents such asdrugs, drug producing cells, cell regeneration factors or evenprogenitor cells of the same type as the involved organ orhistologically different to accelerate healing processes. Paving isdescribed further in U.S. patent application Ser. No. 07/235,998 andInternational Patent Application No. PCT/US89/03593, both of which areincorporated herein by reference.

FIG. 1 shows a six lumen catheter device in accordance with theinvention. In FIG. 1, there are two expansile members 150 and 151, bothconnected to conduit 152. Expansile members 150 and 151 serve to fix theposition of the tubular body 100 within a tissue lumen and isolate thediseased portion of the tissue lumen between them where the therapeuticagent will be applied. Expansile member 153 may be a standardangioplasty balloon or used in deployment of a polymer paving, or both,and is provided with circulating flow via conduits 154 and 155. In thecase that expansile member 153 is used to deploy a polymeric paving,conduits 154 and 155 can be used to provide temperature control to theisolated portion of the tissue lumen, as well as acting to configure thepolymeric coating formed by expanding a polymeric sleeve and otherdeployed form fitted over expansile member 153. The therapeutic agent isprovided from reservoir 159 through conduit 156, with conduit 157 actingas a drain line (or vice versa) to allow flow of fluid through theisolated portion of the tissue lumen ("superfusion"). The drain line isnot required, however, and a simple infusion catheter could omit one ofthe conduits 156 or 157 as in the five lumen designs of FIG. 2 althougha perfusion design is preferred. The sixth conduit 158 is also optional,but can be advantageously used for guide wires, diagnostic ortherapeutic device passage, or distal fluid perfusion. If conduit 158has an aperture proximal to balloon 151, it can be used as a by-passconduit for passive perfusion during occlusion.

The catheter of FIG. 1 can be used in accordance with the method of theinvention to perform procedures such as "bloodless angioplasty" as shownschematically in FIG. 3. In this technique, a catheter 1 is insertedinto a partially blocked blood vessel 2 into the region of the lesion 3.(FIG. 3a) The catheter is positioned such that expansile members 150,151 are disposed on opposite sides of the lesion 3 and expansile members150, 151 are then expanded to isolate a zone 4 around the lesion 3. Theisolated zone 4 is then washed to remove the blood from the region to betreated. This is done by supplying saline or other biocompatiblematerial while removing blood. (FIG. 3b) After the blood is washed fromthe isolated zone 4, a therapeutic agent such as an anti-proliferativeagent is introduced from the reservoir of the catheter. (FIG. 3c)Suitable agents include agents for interfering with nucleic acidsynthesis (e.g., Actinomycin D) or with cell division (e.g. cytochalsinB). Then, after a sufficient period of time has elapsed to allow thetherapeutic agent to be effective, the angioplasty balloon 153 isinflated to disrupt the lesion 3 in accordance with known balloonangioplasty procedure. (FIG. 3d) Additional or different therapeuticagent may be added at this point. The angioplasty balloon 153 in thencontracted. (FIG. 3e) At this stage, a further therapeutic agent or apolymeric coating, with or without admixed antithrombotic orantiproliferative drug, is preferably applied to the area of thedisrupted lesion to facilitate healing. The polymeric coating will alsoprovide a barrier over exposed portions of the media. Finally, theexpansile members 150 and 151 are contracted and the catheter is removedrestoring normal blood flow. (FIG. 3f)

In the treatment of restenosis, the preferred therapeutic agent is ananti-proliferative drug. Useful anti-proliferative drugs are varied instructure and mode of action, and many may be generally viewed asunsuited for therapy during coronary operations under othercircumstances. For example, chemotherapeutic agents which would havesignificant toxic side effects if administered through conventionalroutes (i.e., enteral (oral) or parenteral (intramuscular, IV orsubcutaneous)) can be used with the claimed invention. Thesechemotherapeutic agents include actinomycin D, adriamycin, methotrexate,vinca alkaloids such as colchicine, cytochalsin, vincristine andvinblastine, 5-fluorouracil, and nitrogen mustard.

Other anti-proliferative drugs may also be used including heparins, inboth anti-coagulant and non-anti-coagulant form; anti-proliferativevasodilatory drugs, such as adenosine, cyclic GMP-elevatingvasodilators, angiotensin converting enzyme inhibitors, calcium channelblockers and prostaglandin El; prostacyclin; trapidil, terbinafine,protein kinase C activating phorbol esters and dimethylsulfoxide (DMSO).Fish oil may also be used as an anti-proliferative agent and to inhibitendothelial production of platelet derived growth factor (PDGF). Fishoil could not be administered in a conventional IV mode because of itsinsolubility, but could be used in accordance with the invention.Suramin, a PDGF antagonist with high anti-proliferative profiles buthigh clinical toxicities might also be employed.

Anti-proliferative antibodies to PDGF; or IL-1; TGFb; alpha and gammainterferon; angiopeptin (BIM 23034) and other peptides can also be usedin the invention, although they cannot be administered generally becauseof the risk of an immune response.

Focal treatment with anti-coagulants is also desirable in restenosistreatment to reduce the tendency for clot formation at the PTCA site.These materials could be introduced in solution and allowed to soak intothe vessel wall, or might be deposited as a gel or surfactant coatingwhich adheres to the vessel wall.

As an alternative to the angioplasty balloon as shown in FIG. 1, plaquedisruption can be carried out using a heated balloon to fuse disruptedtissue, as disclosed in U.S. Pat. No. 4,799,479 to Spears or U.S. Pat.No. 4,754,752 to Ginsburg et al.; a woven fibrous tube as disclosed inU.S. Pat. No. 4,650,466 to Luther; or laser light, as disclosed in U.S.Pat. No. 4,445,892 to Hussein et al., U.S. Pat. No. 4,448,188 to Loeb orU.S. Pat. No. 4,627,436 to Leckrone. Solubilizing agents may also beemployed as disclosed by Weikl et al., Wilcox and Wolinsky.

The therapeutic agent used in accordance with the invention may beintroduced in the form of a solution as described above. Alternatively,however, the therapeutic agent may be administered as a gas or in theform of microparticles. For example, as a gas, ethylene oxide, mustardgas or chloroform vapors may be administered in limited doses asantiproliferatives. Microparticles may be formed from the therapeuticagent in combination with biodegradable polymers such as polylacticacid, polyglycolic acid, polycaprolactone, polydioxanone, starch,gelatin and polyanhydrides or nondegradable polymers such as styrene oracrolein. Drug-containing liposomes may also be employed. Preferredsizes of microparticles are less than 4 microns, more preferably lessthan 1 micron (i.e. nanoparticles).

FIG. 4 shows a further catheter which may be used in accordance with theinvention. In this catheter, back-up expansile members 401 and 402 aredisposed outwardly from the principal occluding expansile members 150and 151. This back-up expansile members create a safety zone to preventspill-over of therapeutic agents from the isolated zone 4 into the bloodstream.

Various other modifications to the basic design of the catheter shown inFIG. 1 are also contemplated within the scope of the invention. Forexample, a "weeping" balloon may be employed in place of the standardangioplasty balloon such that materials may be delivered to the isolatedzone through pores in the balloon. Similarly, guidewires may beincorporated in the catheter of the invention, or the two occludingballoons may be disposed on slidably interlocking catheter portions toprovide for adjustable interballoon distances. Finally, one or both ofthe balloons may be equipped with spray ports or nozzles to deliver agas or particulate therapeutic agent to the isolated zone.

The catheter device of the invention may also include a pump or vacuumsystem to deliver the therapeutic agent from the reservoir to the tissuelumen. Such a pump may be servo-controlled to allow for dynamicpressurization of the isolated zone to facilitate diffusion and/oractive penetration of the lesion. Alternate cycling of pressure andvacuum may be advantageously employed to facilitate penetration of thelesion or organ wall.

Other features that may also be included within the catheter of theinvention include heating elements, such as coaxial heating elementswithin one or more sublumens of the catheter body to provide heat to theconduit to facilitate instillation of polymers or surfactants which aresolid at room temperature but which melt with slight heating. Suchheating elements are particularly applicable in the case where apolymeric coating is being formed, either during the introduction oftherapeutic agent or as part of a post-disruption treatment. Thecatheter max also incorporate a high-frequency ultrasound crystal orelement or other acoustically vibrating element between the twoexpansile members to facilitate fluid penetration into the lesion. Suchdevices may also facilitate vibrational or ul;trasonic welding (i.e.,coalescing) or polymer solutions or microparticles leading to theformation of coating on the vessel surface.

In addition, the person skilled in the art will understand thatvariations in the number of lumens within the catheter body may be madewithout departing from the present invention. For example, FIG. 5 showsa seven lumen catheter in which the expansile members which occlude thediseased region are separately controlled through lumens 50 and 51. FIG.6 shows a five lumen superfusion catheter, in which the expansion of theangioplasty balloon is controlled by a single lumen.

While the present invention is ideally suited to the practice ofbloodless angioplasty, it not limited to this application. Indeed, theintroduction of a therapeutic agent focally at the situs of diseaseusing a dual balloon catheter is useful for a wide variety ofindications. In this case, the angioplasty balloon or other disruptivemeans may be omitted from between the two occluding balloons, and thecatheter may be simply a two lumen dual balloon catheter such as thatshown in FIG. 7 connected to a reservoir containing the therapeuticagent. Such a catheter could be used to deliver focal therapy ininstances of bladder tumors, GI polyps, liver tumors, bronchial tumors,renal tumors and uterine tumors. In addition, treatment of inflammatorybowel disease, Crohn's disease, ulcerative colitis and focal GIinflammatory diseases where the application of anti-inflammatory orwound healing composition may prove valuable.

I claim:
 1. A device for providing localized therapy with a therapeuticagent to a diseased region in a tissue lumen, comprising:an elongatetubular shaft having a distal region adapted for insertion into apatient and a proximal region adapted to remain outside of the patient;a monomer or prepolymer solution or an at least partially pre-formedpolymeric product associated with the device so as to be formable into alayer of polymeric material in intimate and conforming contact with anirregularly contoured tissue surface proximal to the distal region ofthe shaft; and a therapeutic agent in fluid communication with thedistal region of the shaft selected to influence the behavior of cells,selected from the group consisting of vasodilating agents, calciumchannel blocking drugs, anti-proliferative agents, intercalating agents,growth modulating factors, and anti-inflammatory agents.
 2. A device asin claim 1, wherein the precursor is a prepolymeric fluid.
 3. A deviceas in claim 2, wherein the prepolymeric fluid contains a therapeuticagent.
 4. A device as in claim 3, wherein the precursor is in at leastpartially polymerized, polymeric article.
 5. A method for providinglocalized therapy to a diseased region in a tissue lumen,comprising:occluding a diseased region in a tissue lumen; removingphysiological fluid from the tissue lumen at the diseased region; andsubsequently disrupting the diseased region of the tissue lumen toloosen diseased tissue.
 6. A method as in claim 5, further comprisingcontacting the occluded region, for a therapeutically effective periodof time, with a therapeutic agent.
 7. A method as in claim 6, whereinthe therapeutic agent is selected from the group consisting ofanti-thrombotic agents, thrombolytic agents, vasodilating agents,calcium channel blocking drugs, anti-proliferative agents, intercalatingagents, growth modulating factors, and anti-inflammatory agents.
 8. Amethod as in claim 5, further comprising the step of paving the diseasedregion of the tissue lumen.
 9. A method as in claim 5, the methodcomprising introducing a device including an elongate tubular shaft intothe tissue lumen, the shaft having a distal region adapted for insertioninto a patient and a proximal region adapted to remain outside of thepatient, an occlusion element at the distal region, and a fluid pathwayconnecting a reservoir at the proximal region with a port at the distalregion.
 10. A method as in claim 9, the device comprising a catheterincluding a flexible elongate tubular shaft and first and secondocclusion elements at the distal region of the shaft, the port locatedbetween the first and second occlusion elements.
 11. A method forproviding localized therapy with a therapeutic agent to a diseasedregion in a tissue lumen, comprising:occluding the diseased region ofthe tissue lumen; contacting the diseased region, for a therapeuticallyeffective period of time, with a therapeutic agent; and paving thediseased region of the tissue lumen.
 12. A method as in claim 11,further comprising, prior to the step of contacting the diseased regionof tissue lumen with the therapeutic agent, the step of removingphysiological fluid from the tissue lumen at the diseased region.
 13. Amethod as in claim 11, the method comprising introducing a deviceincluding an elongate tubular shaft into the tissue lumen, the shafthaving a distal region adapted for insertion into a patient and aproximal region adapted to remain outside of the patient, an occlusionelement at the distal region, a reservoir of therapeutic agent at theproximal region, and a fluid pathway connecting the reservoir at theproximal region with a port at the distal region.
 14. A method as inclaim 13, the device comprising a catheter including a flexible elongatetubular shaft and first and second occlusion elements at the distalregion of the shaft, the port located between the first and secondocclusion elements.
 15. A method as in claim 11, further comprising thestep of disrupting the diseased region of the tissue lumen.
 16. A methodfor providing localized therapy to a diseased region in a tissue lumen,comprising:occluding a diseased region in a tissue lumen; removingphysiological fluid from the tissue lumen at the diseased region; andsubsequently contacting the diseased region, for a therapeuticallyeffective period of time, with a therapeutic agent selected to influencethe behavior of cells, selected from the group consisting ofvasodilating agents, calcium channel blocking drugs, anti-proliferativeagents, intercalating agents, growth modulating factors, andanti-inflammatory agents.
 17. A method as in claim 16, the methodcomprising introducing a device including an elongate tubular shaft intothe tissue lumen, the shaft having a distal region adapted for insertioninto a patient and a proximal region adapted to remain outside of thepatient, an occlusion element at the distal region, a reservoir oftherapeutic agent at the proximal region, and a fluid pathway connectingthe reservoir at the proximal region with a port at the distal region.18. A method as in claim 16, further comprising the step of paving thediseased region of the tissue lumen.
 19. A method as in claim 16,wherein the step of removing physiological fluid comprises washing theoccluded region to remove physiological fluid.
 20. A method as in claim16, the device comprising a catheter including a flexible elongatetubular shaft and first and second occlusion elements at the distalregion of the shaft, the port located between the first and secondocclusion elements.
 21. A method as in claim 16, further comprising thestep of paving the diseased region of the tissue lumen.
 22. A method asin any of claims 5, 11, or 16, wherein the tissue lumen is the interiorof a blood vessel.